N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress

Abstract

-Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated with oxidative stress, and increased levels of reactive oxygen species have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, nondiabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant N-acetylcysteine (NAC), followed by a 2-h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake [tracer-determined disappearance rate (R d), control 41.2 Ϯ 1.7 vs. HG 32.4 Ϯ 1.9 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.05], which was prevented by NAC (HG ϩ NAC 45.9 Ϯ 3.5 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Similar results were obtained with the antioxidant taurine. Neither NAC nor taurine alone altered Rd. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress that was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long-term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance. euglycemic clamp; insulin resistance; protein carbonyls; protein kinase C; antioxidants INSULIN RESISTANCE is one of the earliest detectable predictors of type 2 diabetes (47, 51, 39) and, along with relative insulin deficiency (39, 56), strongly contributes to the development of overt hyperglycemia. Hyperglycemia is in large part responsible for a host of complications found in diabetic subjects (15,83,86) and can worsen insulin resistance (11,38,72,73,75). The effect of hyperglycemia per se to induce insulin resistance in vivo was first demonstrated by Rossetti et al. (75) in the partially pancreatectomized rat model, which is characterized by moderate fasting hyperglycemia, glucose intolerance, and normal fasting insulin levels. In that study, phlorizin was used to normalize plasma glucose without affecting insulin secretion. Use of a hyperinsulinemic-euglycemic clamp revealed that the decreased insulin-stimulated glucose utilization was completely normalized in the phlorizin-treated rats, indicating a direct role of glucose in the induction of insulin resistance. Several mechanisms have been proposed to mediate hyperglycemia-induced insulin resistance, including the hexosamine biosynthetic pathway (4,31,67,74,87) and protein kinase C (55,68,78

Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men

“…Both NAC and TAU, when given i.v. to rats, prevented hyperglycaemia-induced insulin resistancewhich was also thought to be mediated through oxidative stress-and increases in lipid peroxidation products [22]. In humans, lipid-induced insulin resistance correlated with oxidative stress [32][33][34].…”

“…Infusion of the antioxidant N-acetylcysteine (NAC) or taurine (TAU) abolished hyperglycaemia-induced insulin resistance [22]. NAC prevented diabetes in Zucker diabetic fatty rats and ob/ob mice, partly due to its effects on GSIS and preservation of beta cell mass [23].…”

Protein Carbonylation and Adipocyte Mitochondrial Function

“…Oxidative stress and the production of ROS have been strongly implicated as causal in the development of obesitylinked insulin resistance, and a variety of studies have reported that anti-oxidants may have beneficial effects attenuating the characteristics of the metabolic syndrome (3,(35)(36)(37). Increased oxidative stress and production of hydroxyl radicals is linked to the hydroperoxidation of unsaturated acyl chains of membrane lipid and triglyceride.…”

Free Fatty Acid–Induced Reduction in Glucose-Stimulated Insulin Secretion

“…Saline was given as control (equivolume) because we have shown no difference between saline and BSA infusion using the same experimental protocol (12). NAC was given at 2.14 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , the dose that reversed insulin resistance induced by glucose in our previous study (30), and at 2.76 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ; taurine was given at this equimolar dose. Tempol was given at 2.41 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , the dose that showed protection against ROS toxicity in experimental pancreatitis (31).…”